The SELENA study (Safety of Estrogen in Lupus Erythematosus National Assessment) has now demonstrated that estrogen can exacerbate lupus. The data strongly suggest that it is possible to distinguish 2 groups of patients, those who develop multiple disease flares on estrogen and those whose disease is not hormonally modulated. [unreadable] We propose to identify biomarkers to distinguish the 2 groups. We will analyze B cell function after exposure to estradiol; assessing estradiol-mediated protection from BCR triggered apoptosis and estradiol-mediated reduction in BCR signaling. We will analyze estradiol-induced changes in gene expression that distinguish those with a hormonally exacerbated disease from those with a hormonally unresponsive disease. We will look for polymorphisms in the genes encoding estrogen receptors and in estrogen-responsive genes that associate with susceptibility to estrogen-induced worsening of disease. [unreadable] We believe these studies will permit us to learn how to identify lupus patients at risk for an estrogen-induced disease flare. Ultimately, it may be that such patients would benefit from selective estrogen receptor modulators such as tamoxifen or raloxifene or from aromatase inhibitors. Furthermore, these studies will identify cellular pathways involved in disease flares. It cannot be emphasized too much that this study can be performed only in the cohort of patients in the SELENA trial. Another such study will not be performed. [unreadable] [unreadable] [unreadable] [unreadable]